P120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule Ecadherin in the plasma membrane. Its expression is frequently reduced in carcinoma including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. Previous studies have shown that p120-catenin plays important roles in the regulation of proliferation and differentiation of keratinocytes, roles requiring activation of phospholipase C-?1 (PLC-?1). In these cells, extracellular calcium induces the formation of a p120-catenin dependent E-cadherin/catenin complex that recruits and activates phosphatidylinositol 3-kinase (PI3K). PI3K converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 in the plasma membrane then recruits and activates PLC-?1, which by hydrolyzing PIP2 to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) causes an increase in intracellular calcium leading to keratinocyte differentiation. Expression of p120-catenin is reduced in carcinoma cells. Many studies, including ours, have also shown that PLC-?1 mediates epidermal growth factor receptor (EGFR) induced cell proliferation. Expression of PLC-?1 has been found to be elevated in carcinoma cells. These observations have led us to the hypothesis that p120-catenin functions as a tumor suppressor inhibiting OSCC formation by competing with the oncogene EGFR for PLC-?1 activation. The mechanism and location of PLC-?1 activation determine the delicate balance between differentiation and proliferation of keratinocytes. To address this hypothesis, we propose the following specific aims: (1) Determine whether mice lacking p120-catenin are predisposed to carcinogen-induced OSCC formation. (2) Determine whether p120-catenin and EGFR signaling pathways regulate each other. These studies will uncover a tumor suppressor role for p120-catenin in OSCC and provide assessment of predisposing conditions to carcinogenesis, better prevention, better diagnosis, and better treatment of the disease. PUBLIC HEALTH RELEVANCE: p120-catenin is a cytoplasmic protein directly associated with the cell-cell adhesion molecule E- cadherin in the plasma membrane and its expression is frequently reduced in carcinoma cells including oral squamous cell carcinoma (OSCC), but the relationship between p120-catenin and human cancers is unclear. These studies will determine the tumor suppressor role for p120-catenin and provide insight into the mechanism by which p120-catenin protects cells from the development of OSCC. Understanding this mechanism will bring the possibility of new preventive and therapeutic options for OSCC.